The in vivo use of many agents with therapeutic or diagnostic potential is not possible. Larger agents that have in vivo serum half-lives that are sufficiently long to allow for therapeutic or diagnostic efficacy often are unable to penetrate tissues or organs to produces a desired therapeutic or diagnostic effect at a desired location. Smaller agents are able to enter tissues and organs, but frequently have short in vivo serum half-lives, and are rapidly cleared from the systemic circulation. For example, the in vivo serum half-life of dAb monomers is about 30 minutes. (See, Examples 9 and 1.3 of WO 2004/081026 A2.) Similarly, the in vivo serum half-life of antigen-binding fragments of antibodies, particularly Fv fragments, is also short and makes them unsuitable for many in vivo therapeutic and diagnostic applications. (Peters et al, Science 286(5439):434 (1999).) Further, altering or modifying such agents to increase the in vivo serum half-life can reduce the activity of the agent.
A need exists for methods for administering agents (e.g., to pulmonary tissue) to produce a long therapeutic window for the agent.
Agents that bind TNF and neutralize its activity have proven to be effective therapeutic agents for certain inflammatory conditions, such as arthritis. However, agents that bind TNF have not been demonstrated to be effective in treating lung inflammation or respiratory diseases, such as chronic obstructive pulmonary disease (COPD). (See, e.g., van der Vaart et al., Am. J. Respir. Crit. Care Med., 172(4):465-9 (2005), Rennard et al., Proc. Amer. Thorac. Soc., 2(Abstract Issue):A133, A541 (2005), Abdelhady et al., Proc. Amer. Thorac. Soc., 2(Abstract Issue):A133 (2005).) Moreover, therapeutic agents that target TNF alpha, such as ENBREL® (etanercept; Immunex Corporation) antagonize TNFR1 and TNFR2, and administering such agents can produce immunosuppression and related side effects (e.g., serious infections). These side effects can limit the use of such agents, particularly for chronic diseases where the agent is administered over a long period. (Kollias G. and Kontoyiannis D., Cytokine Growth Factor Rev., 13(4-5):315-321 (2002).) In contrast, agents that specifically antagonize TNFR1 would have reduced side effects. However, targeting TNFR1 is difficult because agents that cause the receptor to cluster can activate signaling through the receptor, which can lead to the elaboration of inflammatory mediators such as TNF. In fact, multivalent agents that bind TNFR1, such as anti-TNFR1 antibodies, can induce TNFR1 clustering and signal transduction in the absence of TNF and are commonly used as TNFR1 agonists. (See, e.g., Belka et al., EMBO, 14(6):1156-1165 (1995); Mandik-Nayak et al., J. Immunol, 167:1920-1928 (2001).) Accordingly, multivalent agents that bind TNFR1, are generally not effective antagonists of TNFR1 even if they block the binding of TNFα to TNFR1.
A need exists for improved agents that antagonize TNF and method for administering such agents to treat lung inflammation and lung disease.